There have been increased incidence of bacterial resistance to beta lactam antibiotics in the past 15 years, in spite of the introduction of potent new antibacterial agents belonging to novel 25 chemical classes such as penems, cephems, oxacephems, monobactams, and carbaphenems.
Del Carmen Rodriguez M., et. al. (2004), in their paper, “Phenotypic confirmation of extended-spectrum beta-lactamases (ESBL) in clinical isolates of Escherichia coli and Klebsiella pneumoniae at the San Juan Veterans Affairs Medical Center”, have discussed about ESBLs as an important mechanism of resistance to B-lactam antibiotics in gram-negative bacteria (GNB). They are enzymes that hydrolyze older B-lactam antibiotics as well as broad-spectrum cephalosporins and monobactams.
Jacoby G A., (1994), in his paper “Genetics of extended-spectrum beta-lactamases” described that bacteria have adapted resistance to aztreonam, cefotaxime, ceftazidime, ceftriaxone and other oxyimino-beta-lactams, by altering existing plasmid-mediated class A and class D beta-lactamases.
Niemeyer D M., (1994), in his paper, “Regulation of beta-lactamase induction in gram-negative bacteria: a key to understanding the resistance puzzle,” discusses that infections caused by drug-resistant microorganisms have posed a medical challenge since the advent of antimicrobial therapy. With the emergence of resistant strains, new antibiotics were available and introduced with great success until this decade. The appearance of multiresistant microorganisms poses a real and immediate public health concern.
Danziger L H. and Pendland S L, (1995) in their paper, “Bacterial resistance to beta-lactam antibiotics.” have found that the most commonly prescribed antimicrobials in the United States are the beta-lactam antibiotics, and the most common mechanism of bacterial resistance to these agents is inactivation by beta-lactamase.
Medeiros A A., (1997), in his research paper, “Evolution and dissemination of beta-lactamases accelerated by generations of beta-lactam antibiotics,” has stated that beta-lactamases are the principal mechanism of bacterial resistance to beta-lactam antibiotics.
Ritter E., et al, (1992) in their paper (article in German) “Outbreak of a nosocomial infection of SHV2-beta-lactamase-containing Klebsiella pneumonia strains in an operative intensive care unit.” stated that resistant strains of Klebsiella pneumoniae produced type SHV2-broad-spectrum betalactamase. Thus, the bacteria were resistant to third-generation cephalosporins, such as cefotiam, cefotaxime and ceftriaxone and also to aminoglycosides and acylaminopenicillins.
S. J. Cavalieri, et al, (1991) in their paper, “Influence of beta-lactamase inhibitors on the potency of their companion drug with organisms possessing class I enzymes,” undertook a study which was designed to assess the ability of sulbactam and clavulanate to induce beta-lactamases in two strains each of Enterobacter cloacae, Citrobacter freundii, Serratia marcescens, and Pseudomonas aeruginosa both in vitro and in vivo. The data suggest that beta-lactamase inhibitors can influence the in vivo potency of their companion drug.
Ghatole M., et al, (2004), in their paper, “Correlation of extended spectrum beta-lactamases production with cephalosporin resistance in gram negative bacilli”, discussed that beta-lactamase production is an important mechanism of developing resistance to beta lactam group of antibiotics. Cephalosporins with extended spectrum of activity and stability were introduced to overcome this resistance, but soon production of extended spectrum beta lactamase (ESBLs), which are inducible in nature was reported.
Lopez-Hernandez S. et al, (1999) in their paper, “In vitro activity of beta-lactam agents and beta-lactamase inhibitors in clinical isolates of Acinetobacter baumannii”, compared the in vitro activity of betalactam agents, (ampicillin, piperacillin and ticarcillin), betalactamase inhibitors (clavulanic acid, sulbactam and tazobactam) alone and in combination with betalactam agents (amoxicillin-clavulanic acid, ampicillin-sulbactam, piperacillin-tazobactam and ticarcillin-clavulanic) against 156 clinical isolates of A. baumannii. Sulbactam was the only betalactamase inhibitor which showed good in vitro activity, with a low MIC (50) and MIC (90) (and 32 mg/l, respectively) similar to ampicillin/sulbactam (2 and 16 mg/l, respectively). Sulbactam could be good therapeutic alternative for the treatment of multiresistant A. baumannii infections.
Sadar H S., et al, (2000) in their paper, “Comparative evaluation of the in vitro activity of three combinations of beta-lactams with beta-lactamase inhibitors: piperacillin/tazobactam, ticarcillin/clavulanic acid and ampicillin/sulbactam”, found that ticarcillin/clavulanic acid was active against 85.8% of the Enterobacteriaceae, while ampicillin/sulbactam inhibited 83.2% of the samples.
Finegold S M, (1999) in his paper, “In vitro efficacy of beta-lactam/beta-lactamase inhibitor combinations against bacteria involved in mixed infections”, found that the mixed infections are usually caused by a relatively limited range of bacteria, with the anaerobes and opportunistic pathogens contributing to their severity. In order to make the best therapeutic choice for a patient with a life-threatening infection, which is probably of mixed etiology, clinicians must be aware of the organisms that are likely to be involved, and the fact that most of them will produce beta-lactamase. Of the options available for empiric therapy, the beta-lactam/beta-lactamase inhibitor combinations represent a good choice. Their antibacterial spectra include both aerobic and anaerobic pathogens.
It is clear that there is a need to provide an inexpensive antibiotic formulation that will be effective against the increasing variety of beta lactamase-producing bacterial strains. There is also a need for such formulations to be provided in parenterally administrable form. There is also a need to develop antibiotic formulations that will not lead to rapid emergence of resistant bacterial strains.